Biologics targeting IL-17 sharply reduce circulating T follicular helper and T peripheral helper cell sub-populations in psoriasis

IntroductionCirculating T follicular helper (cTfh) cells and circulating T peripheral helper (cTph) cells (which share common characteristics with the cTfh population) are implicated in the pathogenesis of immune-mediated and autoimmune diseases such as psoriasis (Ps). Their close interplay with the interleukin 17 (IL-17) axis and the ex vivo effect of IL-17-targeting biologic agents used to treat Ps on them are elusive. This study aimed to investigate the effect of biologics targeting IL-17 on cTfh and cTph cell subpopulations isolated from the blood of patients with Ps.MethodsPeripheral blood mononuclear cells (PBMCs) were isolated from patients with Ps at treatment initiation and three months later. Samples were also collected from controls. Cells were stained using monoclonal antibodies. Flow cytometry assessed the fraction of cTfh (CD3+CD4+CXCR5+) and cTph (CD3+CD4+CXCR5-PD-1hi) cells..ResultsFlow cytometric analysis showed increased fractions of activated cTfh subsets including ICOS+ and ICOS+PD-1+ expressing cells, in patients compared to controls. Biologic blocking of IL-17A diminished the cTfh population. Furthermore, ICOS+ and ICOS+PD-1+ sub-populations were also inhibited. Finally, the cTph cell fraction significantly decreased after three months of successful treatment with biologics.ConclusionEarly anti-IL-17-mediated clinical remission in Ps is associated with decreased cTfh and cTph cell subpopulations

Immunopathogenesis of primary biliary cirrhosis: an old wives' tale

Primary biliary cirrhosis (PBC) is a cholestatic liver disease characterised by the autoimmune destruction of the small intrahepatic bile ducts. The disease has an unpredictable clinical course, but may progress to fibrosis and cirrhosis. Although medical treatment with urseodeoxycholic acid is largely successful, some patients may progress to liver failure requiring liver transplantation. PBC is characterised by the presence of disease specific anti-mitochondrial (AMA) antibodies, which are pathognomonic for PBC development. The disease demonstrates an overwhelming female preponderance and virtually all women with PBC present in middle age. The reasons for this are unknown; however several environmental and immunological factors may be involved. As the immune systems ages, it become less self tolerant, and mounts a weaker response to pathogens, possibly leading to cross reactivity or molecular mimicry. Some individuals display immunological changes which encourage the development of autoimmune disease. Risk factors implicated in PBC include recurrent urinary tract infection in females, as well as an increased prevalence of reproductive complications. These risk factors may work in concert with and possibly even accelerate, immune system ageing, contributing to PBC development. This review will examine the changes that occur in the immune system with ageing, paying particular attention to those changes which contribute to the development of autoimmune disease with increasing age. The review also discusses risk factors which may account for the increased female predominance of PBC, such as recurrent UTI and oestrogens

ELECTRON: An Architectural Framework for Securing the Smart Electrical Grid with Federated Detection, Dynamic Risk Assessment and Self-Healing

The electrical grid has significantly evolved over the years, thus creating a smart paradigm, which is well known as the smart electrical grid. However, this evolution creates critical cybersecurity risks due to the vulnerable nature of the industrial systems and the involvement of new technologies. Therefore, in this paper, the ELECTRON architecture is presented as an integrated platform to detect, mitigate and prevent potential cyberthreats timely. ELECTRON combines both cybersecurity and energy defence mechanisms in a collaborative way. The key aspects of ELECTRON are (a) dynamic risk assessment, (b) asset certification, (c) federated intrusion detection and correlation, (d) Software Defined Networking (SDN) mitigation, (e) proactive islanding and (f) cybersecurity training and certification

Curcumin for the Management of Periodontitis and Early ACPA-Positive Rheumatoid Arthritis: Killing Two Birds with One Stone

We propose curcumin as a preventive measure to avoid/manage periodontitis (PD), and as a natural immunosuppressant for rheumatoid arthritis (RA). PD, mainly caused by Porphyromonas gingivalis forming biofilm and leading to tooth decay, is a major public health issue and a risk factor for the development of RA in humans. P. gingivalis is able to trigger experimental autoimmune arthritis in animal models and in humans can induce citrullinated peptides, which not only are a source of anti-citrullinated antibodies (ACPAs), but also participate in autoreactive responses and disease development. Curcumin appears to have efficient anti-bacterial activity against P. gingivalis infection and biofilm formation. In addition to antibacterial, anti-oxidant, and anti-inflammatory action, curcumin exerts unique immunosuppressant properties via the inhibition of Th17 pro-inflammatory responses and promotion of regulatory T cells, thus suppressing autoimmunity. We introduce curcumin as a natural product for the management of both PD and RA-related autoreactivity, possibly also as a preventive measure in early RA or individuals at high risk to develop RA

The Role of Flavonoids in Inhibiting Th17 Responses in Inflammatory Arthritis

Flavonoids have been considered powerful anti-inflammatory agents, and their exact immunomodulatory action as therapeutic agents in autoimmune diseases has started to emerge. Their role in the manipulation of immunoregulation is less understood. Several studies attempted to investigate the role of various flavonoids mainly in experimental models of autoimmune diseases, especially in the context of their potential effect on the increase of regulatory T cells (Tregs) and their ability to stimulate an overexpression of anti-inflammatory cytokines, in particular that of IL-10. The emergence of IL-17, a cytokine largely produced by Th17 cells, as a powerful proinflammatory stimulus which attenuates the induction of Tregs has prompted a series of studies investigating the role of flavonoids on Th17 cells in experimental models as well as human autoimmune diseases. This review thoroughly discusses accumulated data on the role of flavonoids on Th17 in rheumatoid arthritis and experimental autoimmune arthritis

The Role of Invariant NKT in Autoimmune Liver Disease: Can Vitamin D Act as an Immunomodulator?

Natural killer T (NKT) cells are a distinct lineage of T cells which express both the T cell receptor (TCR) and natural killer (NK) cell markers. Invariant NKT (iNKT) cells bear an invariant TCR and recognize a small variety of glycolipid antigens presented by CD1d (nonclassical MHC-I). CD1d-restricted iNKT cells are regulators of immune responses and produce cytokines that may be proinflammatory (such as interferon-gamma (IFN-γ)) or anti-inflammatory (such as IL-4). iNKT cells also appear to play a role in B cell regulation and antibody production. Alpha-galactosylceramide (α-GalCer), a derivative of the marine sponge, is a potent stimulator of iNKT cells and has been proposed as a therapeutic iNKT cell activator. Invariant NKT cells have been implicated in the development and perpetuation of several autoimmune diseases such as multiple sclerosis and systemic lupus erythematosus (SLE). Animal models of SLE have shown abnormalities in iNKT cells numbers and function, and an inverse correlation between the frequency of NKT cells and IgG levels has also been observed. The role of iNKT cells in autoimmune liver disease (AiLD) has not been extensively studied. This review discusses the current data with regard to iNKT cells function in AiLD, in addition to providing an overview of iNKT cells function in other autoimmune conditions and animal models. We also discuss data regarding the immunomodulatory effects of vitamin D on iNKT cells, which may serve as a potential therapeutic target, given that deficiencies in vitamin D have been reported in various autoimmune disorders